The present invention relates to a remedy for drug dependence. In addition, the present invention relates to a dopamine-release inhibitor, in which dopamine is heavily associated with drug dependence.
When a person repeatedly take a natural substance such as opium, cocaine, or marijuana, or takes a specific drug such as heroin, barbiturates, or stimulants, it is impossible to suddenly withhold the drug. Then, their major goal in life tends to focus on obtaining these substances and drugs. In addition, brutal crimes may be provoked. Moreover, serious incidents, which affect the state of the nation, may also be provoked. There is substantially the same underlying cause in these problems of drug abuse as in habituation to consuming common substances, for example, alcohol or tobacco.
World Health Organization (WHO) defines both drug dependence and drug abuse. That is, drug dependence is defined as follows: xe2x80x9cA state, psychic and sometimes also physical, resulting from the interaction between a living organism and a drug, characterized by behavioural and other responses that always include a compulsion to take the drug on a continuous or periodic basis in order to experience its psychic effects, and sometimes to avoid the discomfort of its absence.xe2x80x9d Drug dependence is further classified as a state of psychic dependence on a drug, that is, psychic dependence, or a state in which a body is adapted to existing the drug, that is, physical dependence.
The WHO classifies drugs which become addictive into nine groups, that is, 1. alcohol, 2. amphetamines, 3. barbiturates, 4. marijuana, 5. cocaine, 6. hallucinogens, 7. khat, 8. opiates, and 9. organic solvents. All the drugs classified into the nine groups, to which dependence may be developed, also show psychic dependence. In addition, three groups, that is, opiates, barbiturates, and alcohol, may be accompanied by physical dependence. At present, among these drugs which develop dependence, opiates, barbiturates, cocaine, and amphetamines are available for clinical use.
With respect to international laws relevant to dependence-producing drugs, there are the xe2x80x9cSingle Convention Treaty on Narcotic Drugsxe2x80x9d (1961) and the xe2x80x9cThe Convention on Psychotropic Substancesxe2x80x9d (1971). Under the above-mentioned two treaties, all countries are to make a concerted effort to conduct strict inspections of international distribution of narcotics and prevent narcotics from being illicitly distributed. As drug abuse expands throughout the world, international regulation becomes stricter. Recently, drugs capable of being abused have increased both in kind and in variety. On the other hand, since exchange of goods and travel have been internationally increased and an information network has been developed, cases of psychotropic drug abuse have increased in addition to cases of narcotics, marijuana, and stimulant abuse. In addition, the drug abuse epidemic area is also spreading throughout the world. For example, recently, narcotics abuse has significantly increased in countries in North America, Central and South America, Southeast Asia, Middle East, and Europe. In particular, the cocaine abuse problem has become a deep social ill in South America, North America, Europe and the like. On the other hand, the stimulants abuse problem has also spread in Japan, North America, and Europe. Furthermore, at present, other psychotropic drug abuses have also increased in these countries.
With respect to a remedy for drug dependence, particular drugs are not usually applied other than drugs used for symptomatic treatment. The main treatment is psychotherapy which is aimed at self-awareness, replacing a dependence-producing drug with a drug which is less dependent, or gradually-decreasing drug treatment. With respect to symptomatic treatment, antianxiety drugs such as diazepam and flunitrazepam, and short-acting barbiturates have been initially used for treatment for acute toxipathy. An antipsychotic agent such as haloperidol or phenotiazines has been used for treatment of acute psychoses. However, the items of concern involve adverse effect such as psychogenesis peculiar to central nervous system sedatives in treatments using drugs such as diazepam, flunitrazepam, or barbiturates. The items of concern involve adverse effects such as psychogenesis peculiar to psychotropic drugs in treatment using drugs such as haloperidol or phenotiazines, so that there is the possibility that drug dependence is replaced by psychotropic drug dependence. (Alcohol and Drug Dependence, Basic Research and Clinical Research, Kenshirou Oohara, Sakutarou Tadokoro (Kaneharasyuppan); Drug Dependence, Mitsumoto Satou, Susumu Fukui (Sekaihokentuusinsya)).
A drug reaction in which after the drug is given to a living organism, drug-seeking behavior or drug-taking behavior are more frequently induced, is defined as a reinforcing effect or a reward effect. These effects caused by the dependence-producing drugs are closely related to an intracerebral dopamine nervous system. The intracerebral dopamine nervous system is roughly classified into two systems, that is, a nigrostriatal system and a mesolimbic system which projects from an ventral tagmental area to a nucleus accumbens. There have been many reports which indicate the reinforcing effect or the reward effect is related to the mesolimbic system.
For example, cocaine, that is a central nervous system stimulant, affects neurosynapses in the nucleus accumbens so as to accelerate dopamine release from dopamine neuroterminals and to inhibit the uptake thereof, so that an amount of dopamine which binds to dopamine receptors increases and nerve activities are facilitated. Therefore, onset of psychic dependence seems to be triggered. On the other hand, since opioid xcexa receptor agonists inhibit dopamine release in the nucleus accumbens (Japanese Journal of Pharmacology. 109: 165-173, 1997), the opioid xcexa receptor agonists may suppress the reward effect of cocaine and hold promise as a remedy for psychic cocaine dependence. At present, opioid xcexa receptor agonists, however, have not been applied in practical use for a remedy for cocaine dependence.
In addition, with respect to the relationship between opiates and their reward effect in drug dependence, it is known that opiates not only have analgesic activity but also function as a chemical mediator for the reward effect. The opioid receptors are classified into xcexc, xcex4, and xcexa receptors. Among them, it was initially reported that xcexc receptor agonists such as morphine showed the reward effect (T. Suzuki et al., Eur. J. Pharmacol. 205, 85, 1991). It has been reported that xcexc or xcex4 receptor agonistic endogenous opioid peptides such as xcex2-endorphins and enkephalins also show the reward effect (T. Suzuki et al., Jpn. J. Pharmacol. 66, 131, 1994).
Furthermore, opioid receptors are known to relate to a dopamine nervous system. The opioid xcexc receptors are distributed in high density in a ventral tegmental area in which cell sonata of the mesolimbic system exist, so that they inhibit an inhibitory xcex3-aminobutyric acid (GABA) nervous system, that is, interneurons, and stimulate the mesolimbic system. As a result, it is suggested that when a xcexc receptor agonist is systemically administered or microinjected into the ventral tegmental area, dopamine release in the projected nucleus accumbens seems to be significantly increased. On the other hand, xcex4, and xcexa opioid receptors are known to be distributed in high density in the projected area, that is, nucleus accumbens in the mesolimbic system. When xcex4 opioid receptors are activated, similarly to xcexc opioid receptors, they seem to inhibit the inhibitory GABA nervous system, that is, interneurons, and to facilitate dopamine release in the nucleus accumbens. In contrast, xcexa receptor agonists do not show the reward effect in a drug self-administration (T. Suzuki et al., Brain Res. 602, 45, 1993). As described above, it is reported that when a xcexa receptor agonist such as U-50488H which activates xcexa receptors is administered, dopamine release from the nucleus accumbens is inhibited (Japanese Journal of Pharmacology. 109: 165-177, 1997). In addition, animal tests show that -the reward effect induced by xcexc or xcex4 receptor agonists is inhibited by xcexa receptor agonists such as U-50488H (M. Funada et al., Neuropharmacology, 32, 1315, 1993). That is, activation of xcexa receptors enhances an analgesic effect of xcexc or xcex4 receptor agonists, but inhibits the reward effect. On the basis of these facts, opioid xcexa receptor agonists seem to be promising remedies for psychic dependence to opioid xcexc receptor agonists. Furthermore, it is reported that opioid xcexa receptor antagonists enhance development of physical dependence, but certain opioid xcexa receptor agonists inhibit development of physical dependence (Suzuki, T. et al., Eur. J. Pharmacol. 213, 91, 1991). At present, opioid xcexa receptor agonists, however, have not been adapted to remedies for opioid xcexc receptor agonists dependence and also have not been applied in practical use.
In a reported case of opioids and nicotine dependence (tobacco addiction), naloxone, that is, a narcotic antagonist (xcexc receptor antagonist), is effective for a reduction in intake of tobacco of chronic smokers for three hours in a double blind test and a cross-over test with a drug and its placebo (Karras, A. et al., Life Science, 27, 1541, 1980). In contrast, it is reported that naloxone accelerates a withdrawal syndrome in rats with nicotine dependence, and morphine (a xcexc receptor agonist) inhibits the withdrawal syndrome after an administration of nicotine (Malin, D. H. et al., Psychopharmacology, 112, 339, 1993). In addition, it is reported that nicotinic receptors exist at terminals of a dopamine nervous system in the nucleus accumbens, and relate to facilitation of dopamine release (Di Chiara, G. et al., Natl. Acad. Sci. USA, 85, 5274, 1988). Furthermore, it is reported that a reduction in the amount of dopamine in the nucleus accumbens follows the cessation of the administration of nicotine to rats with nicotine dependence (Fung, Y. K. et al., J. Pharm. Pharmacol., 41, 66, 1989). In contrast, inhibitory activity against nicotine dependence of xcexa receptor agonists including dynorphin which is an endogenous opioid peptide having xcexa receptor agonistic activity, particularly inhibitory activity against physical dependence, has not been clear.
In addition, there have been many reports that psychic dependence on a drug such as barbiturates, benzodiazepines which are central nervous system sedatives, amphetamine, methamphetamine, and the like which are stimulants, phencyclidine which is a hallucinogen, and alcohol is controlled by a mechanism of dopamine increase (Yanagita T., Nippon Yakugaku Zasshixe2x80x94Folia Pharmacologica Japonica. 100 (2): 97-107, 1992 Aug.; Samochowiec J., Annales Academiae Medicae Stetinensis. 40: 195-217 (1994); Kuperman D I. et al., Brain Research. 771 (2): 221-7 (1997); Heron C. et al. European Journal of Pharmacology. 264 (3): 391-8 (1994); Saad S F. et al. Journal of Pharmacy and Pharmacology. 49 (3): 322-8 (1997); Costall B. et al., Arzneimittel-Forschung. 42 (2A): 246-9 (1992)). On the basis of the above-described facts, drugs having activity to inhibit dopamine release from the nucleus accumbens may inhibit the reward effect caused by these dependence-producing drugs and may be a promising remedy for psychic dependence.
In addition, existing highly selective xcexa receptor agonists such as U-50488H prove not to develop drug dependence which is a characteristic of morphine or the like having reactivity to a xcexc receptor (T. Suzuki et al., Eur. J. Pharmacol., 205, 85, 1991).
An object of the present invention is to provide a remedy for drug dependence with little adverse effects, which depresses not only onset of psychic dependence but also physical dependence due to controlling the expression mechanism of the reward effect of dependence-producing drugs in a treatment for drug dependence caused by cocaine, opioid xcexc agonists, nicotine, alcohol, stimulants, barbiturates, benzodiazepines, or hallucinogens. The above-mentioned treatment is different from the conventional symptomatic treatments.
The present invention provides a remedy for drug dependence in which the active ingredient is an opioid xcexa receptor agonist. In addition, the present invention also provides a dopamine-release inhibitor in which the active ingredient is an opioid xcexa receptor agonist.